Getting the Dose Right The View from Academia

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Presentation on theme: "Getting the Dose Right The View from Academia"— Presentation transcript:

1Getting the Dose Right The View from AcademiaGL Drusano, M.D.Co-DirectorOrdway Research Institute &Research PhysicianNY State Department of HealthDirectorDivision of Clinical PharmacologyAlbany Medical College

2Getting the Dose Right The View from AcademiaWhat are the determinants of “getting the dose right”?The first question that needs to be addressed is “What outcome is desired”?Multiple outcomes are reasonable -Good clinical outcome -Good microbiological outcome -Suppression of resistance -Minimization of concentration-related toxicities

3Getting the Dose Right The View from AcademiaDose choice becomes an issue in the Phase-I time frame (actually earlier, but the proper data becomes available at this time)Because of this, the choice of outcome is somewhat limited – Clinical outcome cannot, at this time, be an outcome measureThe most common measure, then, is microbiological outcome determined from in vitro or animal models

5Getting the Dose Right The View from AcademiaOnce a target exposure is chosen, what other pieces of information are required? -Population PK: this quantifies the variability in how the drug dose is handled by a population -MIC distribution for the target pathogens: this quantifies how the MIC will vary -Protein binding: in general, only free drug is microbiologically active

6Getting the Dose Right The View from AcademiaNow we can evaluate how well a specific drug dose will attain the desired targetThis evaluation will be done employing Monte Carlo simulation

8Getting the Dose Right The View from AcademiaWhat are the questions now? -Was the target correct? -Is the target attainment rate adequate?The target [1 log10 (CFU/g) decline] is reasonably conservative, but one must be careful about the infection siteThe answer to the second question depends on the patient and the consequences of being wrong: -G-penic patient vs uncomplicated SSTI -Mother vs Mother-In-Law

9Getting the Dose Right The View from AcademiaWhat now?Now it is important to recapitulate the analysis in real patients in the Phase I/II environmentWhy?The PK is determined in a target populationCorrelation with preclinical animal data provides near certainty of “no surprises” in Phase III“real world” organisms are seen and can be gauged against the original MIC distributionsMonte Carlo simulations can be re-calculated with “real” data

18Getting the Dose Right The View from AcademiaAll regimens were simultaneously fit in a large population modelThe displayed graph is the predicted-observed plot for the total population after the Maximum A-posteriori Probability (MAP) Bayesian step

19Getting the Dose Right The View from AcademiaAll regimens were simultaneously fit in a large population modelThe displayed graph is the predicted-observed plot for the resistant population after the Maximum A-posteriori Probability (MAP) Bayesian step

22Getting the Dose Right The View from AcademiaIn this experiment, a dose was selected to generate an exposure that would prevent emergence of resistanceAs this was at the limit of detection, the measured population sometimes had “less than assay detectable” for the colony countThese were plotted at the detection limitJournal of Clinical Investigation 2003;112:

23Getting the Dose Right The View from AcademiaWe were able to determine how the overall (sensitive plus resistant) population responds to pressure from this fluoroquinoloneMore importantly, we were able to model the resistant subpopulation and choose a dose based on simulation to suppress the resistant mutantsThe prospective validation demonstrated that the doses chosen to encourage and suppress the resistant mutants did, indeed, work

24Getting the Dose Right The View from AcademiaWhat about having a high probability of attaining a good outcome while not encumbering the patient with a high probability of a concentration-related toxicity?For this we will examine aminoglycosides, where we have concentration-effect and concentration-toxicity probability relationships

29Getting the Dose Right The View from Academia-ConclusionsWhy go through all this mathematical *!$# ? -Because, at the end of the therapy is a patient, who would appreciate getting better without toxicity -Also, because choosing the dose correctly allows trials with anti-infectives to have the lowest Phase III failure rate of ANY therapeutic area